Staphylococcus aureus infections of the bloodstream, lung, surgical sites, and skin and soft tissues are a leading cause of morbidity and mortality. The attributable mortality associated with methicillin sensitive S. aureus bloodstream infection is 19% and this rises to 33% if S. aureus is methicillin resistant(MRSA). More than 50% of S. aureus clinical isolates at DVAMC-Denver are methicillin-resistant, and MRSA is endemic in many VA hospitals nationwide, leading to national efforts to control the problem. Nasal colonization with S. aureus is a source of transmission to other persons, and a major risk factor for subsequent infection in colonized individuals. For example, patients who are colonized at the time of hospital admission have a three-fold higher risk of bloodstream infection with S. aureus, and preliminary data from DVAMC-Denver indicate that MRSA colonization is associated with an 8-fold increased risk for MRSA bacteremia. Decolonization therapy reduces the risk of infection, supporting the hypothesis that colonization leads to infection. We hypothesize that nasal commensal microbes (the nasal microbiome) may inhibit or promote S. aureus nasal colonization. Results from a cross-sectional study of hospital inpatients support this hypothesis. Previous studies of microorganisms competing with S. aureus for the anterior nares niche have focused on individual species, e.g. Staphylococcus epidermidis, Streptococcus pneumoniae, Corynebacterium spp., isolated from culture. There is a growing body of evidence that microorganisms exist in nature as consortia, and that study of them in this fashion may advance our understanding of their competitive environment. The microbial consortia that normally inhabit the nasal cavity may be difficult to culture on routine media, so its impact on S. aureus colonization remains poorly characterized. To identify microbial species associated with a lower risk of MRSA colonization, we propose to prospectively characterize the human nares microbiota in a well-defined cohort of subjects. A program of active screening of hospital inpatients for nasal MRSA colonization is part of the VHA national effort to control MRSA in hospitalized veterans, and provides an opportunity to gather samples in a longitudinal fashion, clearly define persons as non-carriers, persistent carriers or intermittent carriers, and identify differences between these groups in nasal microbiota. We will comprehensively determine the nares microbiota in specimens collected longitudinally, using innovative DNA sequence-based technologies (16S rRNA metagenomics) and correlate these data with MRSA colonization and infection. Our understanding of the complex interactions among populations of bacteria is only beginning, and may lead to new strategies that can be harnessed to improve human health. Possibilities include development of probiotic therapies, identification of bacteriocins produced by MRSA-inhibitory commensals, which may be applied to the nares or other body sites to prevent colonization, and synthesis of small molecule congeners of bacteriocins that may be useful as systemic antibacterial agents.